DESCRIPTION: This proposal is a continuation of our studies which attempt to elucidate the molecular bases of cirrhosis in alcoholic liver disease. Hepatic fibrogenes caused by alcohol abuse or other etiologies is a complex process that involves a balance between liver cell proliferation and cell death, as well as the increased deposition and modeling of extracellular matrix (ECM) proteins. Our recent studies provide evidence for the significance of one factor, tissue transglutaminase (tTG), in many of these interactions. This ubiquitous enzyme has characteristics that may induce either apoptosis or cell proliferation, and it appears to contribute to the fibrotic process in a number of ways. This proposal is an attempt to elucidate the mechanisms by which tTG affects the process of hepatic mitogenesis or apoptosis, especially as it pertains to ethanol administration. Specific Aims: 1) To determine the pathways and functional significance of alpha-1 adrenergic signaling in hepatocytes; 2) To investigate the downstream effects of alpha-1 adrenergic signaling on hepatocyte mitogenesis; and 3) To delineate the mechanisms by which tTGase cross-linking activity inhibits proliferation and enhances apoptosis in hepatocytes. These studies will entail determining whether phenylephrine-induced hepatocyte mitogenesis acts through alpha-1B adrenergic receptor binding coupled to the tTGase G-protein subunit, Galphah, whether this activates the MAPK pathway, and by what mechanism this activation may be occurring. In addition, the mechanism by which tTGase cross-linking activity may affect upstream events in the apoptosis cascade will also be explored. Health Relatedness: It is hoped that by better understanding the molecular mechanisms by which ethanol affects fibrogenesis, hepatic mitogenesis, and apoptosis, more effective and rational therapeutic intervention may be developed.